Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen

The rise of multi-drug-resistant (MDR) bacteria has spurred renewed interest in the use of bacteriophages in therapy. However, mechanisms contributing to phage-mediated bacterial clearance in an animal host remain unclear. We investigated the effects of host immunity on the efficacy of phage therapy for acute pneumonia caused by MDR Pseudomonas aeruginosa in a mouse model. Comparing efficacies of phage-curative and prophylactic treatments in healthy immunocompetent, MyD88-deficient, lymphocyte-deficient, and neutrophil-depleted murine hosts revealed that neutrophil-phage synergy is essential for the resolution of pneumonia. Population modeling of in vivo results further showed that neutrophils are required to control both phage-sensitive and emergent phage-resistant variants to clear infection. This “immunophage synergy” contrasts with the paradigm that phage therapy success is largely due to bacterial permissiveness to phage killing. Lastly, therapeutic phages were not cleared by pulmonary immune effector cells and were immunologically well tolerated by lung tissues. [Display omitted] •Efficacious phage therapy to pulmonary P. aeruginosa requires innate immune components•Neutrophils are required to control phage-sensitive and emergent phage-resistant bacteria•Models predict “immunophage synergy” arises due to nonlinear feedback The mechanisms underlying phage-mediated bacterial clearance in an animal host remain unclear. By coupling animal experiments and in silico modeling, Roach et al. show that host innate immunity is essential for the efficacy of phages in treating respiratory bacterial infections, defining the concept of “immunophage synergy.”